title: Mutator activity induced by microRNA-155 (miR-155) links inflammation and cancer.
abstract: Infection-driven inflammation has been implicated in the pathogenesis of ~15-20% of human tumors. Expression of microRNA-155 (miR-155) is elevated during innate immune response and autoimmune disorders as well as in various malignancies. However, the molecular mechanisms providing miR-155 with its oncogenic properties remain unclear. We examined the effects of miR-155 overexpression and proinflammatory environment on the frequency of spontaneous hypoxanthine phosphoribosyltransferase (HPRT) mutations that can be detected based on the resistance to 6-thioguanine. Both miR-155 overexpression and inflammatory environment increased the frequency of HPRT mutations and down-regulated WEE1 (WEE1 homolog-S. pombe), a kinase that blocks cell-cycle progression. The increased frequency of HPRT mutation was only modestly attributable to defects in mismatch repair machinery. This result suggests that miR-155 enhances the mutation rate by simultaneously targeting different genes that suppress mutations and decreasing the efficiency of DNA safeguard mechanisms by targeting of cell-cycle regulators such as WEE1. By simultaneously targeting tumor suppressor genes and inducing a mutator phenotype, miR-155 may allow the selection of gene alterations required for tumor development and progression. Hence, we anticipate that the development of drugs reducing endogenous miR-155 levels might be key in the treatment of inflammation-related cancers.
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Medical Center, Columbus, OH 43210, USA.
authors.forename: Esmerina
authors.initials: E
authors.lastname: Tili
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Michaille
authors.forename: Dorothee
authors.initials: D
authors.lastname: Wernicke
authors.forename: Hansjuerg
authors.initials: H
authors.lastname: Alder
authors.forename: Stefan
authors.initials: S
authors.lastname: Costinean
authors.forename: Stefano
authors.initials: S
authors.lastname: Volinia
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D016147:Genes, Tumor Suppressor; D057809:HEK293 Cells; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D013866:Thioguanine / Q000494:pharmacology
chemical_list: D000964:Antimetabolites, Antineoplastic; D018797:Cell Cycle Proteins; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D007041:Hypoxanthine Phosphoribosyltransferase; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; D013866:Thioguanine